BIOL 320: Genetics (Chapters 6, 7)

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*Making a Karyotype* • A few drops of blood are added to a flask containing a mitosis-inducing chemical such as phytohemagglutinin, and the cells are grown for 2 or 3 days at body temperature (37 C) in an incubator • A drug such as Colcemid is then added, and about 2 hours after, all cells entering mitosis stop dividing when they enter metaphase • The treated cells are collected and concentrated by centrifugation • Adding a salt solution breaks open and destroys the red blood cells and swells the lymphocytes • After fixation in a mixture of methanol and acetic acid, the swollen lymphocytes are dropped onto a microscope slide; the impact causes the fragile cells to break open, spreading metaphase chromosomes onto the slide • The chromosome preparation is partially digested with trypsin, and enzyme that enhances the banding pattern • After staining, the preparation is examined with a microscope, and a cluster of metaphase chromosomes is located on the slide • A video camera attached to the microscope transmits the chromosome images to a computer, where they are recorded, digitized, and process to make a karyotype

copy number variation (CNV)

A DNA segment at least 1,000 base pairs long with a variable copy number in the genome. They change the structure of the genome and, along with submicroscopic inversions and translocations, are all forms of genome structural variation.

tetraploidy

A chromosomal number that is four times the haploid number, having four copies of all autosomes and four sex chromosomes. • Can result from a failure of cytokinesis in the first mitotic division after fertilization • If this condition arises at some point after the first mitotic division, two different cell types will be present in the embryo: normal diploid cells and tetraploid cells • Such mosaic individuals survive somewhat longer than do full tetraploids, but the condition is still life-threatening

uniparental disomy (UPD)

A condition in which both copies of a chromosome are inherited from one parent. It can arise in several ways, all of which require two chromosomal errors in cell division. These errors can occur in meiosis or in mitotic divisions after fertilization.

fetal alcohol syndrome (FAS)

A constellation of birth defects caused by maternal alcohol consumption during pregnancy. • Between 0.5 and 2.0 affected infants per 1,000 births • Can result in miscarriage, growth retardation, facial abnormalities, mental retardation and learning disabilities • Teratogenic effects of alcohol can occur at any time during pregnancy, but weeks 8 to 12 are particularly sensitive periods • Having six drinks in one day and none the rest of the week is worse than having a drink every day of the week

Cri du chat syndrome (5p-)

A deletion of the short arm of chromosome 5 associated with an array of congenital malformations, the most characteristic of which is an infant cry that resembles a meowing cat. • Occurs in 1 in 20,000 to 1 in 50,000 births • Affected individuals are mentally retarded, with defects in facial development and an abnormal larynx • The deletion affects the motor and mental development of affected individuals but does not seem to be life-threatening

the Lyon hypothesis

A hypothesis about how dosage compensation works: • Only one X chromosome is genetically active in the body cells of female mammals; the second X chromosome is inactivated and tightly coiled to form the Barr body • The inactivated chromosome can come from either parent • Inactivation takes place early in development; After four to five rounds of mitosis following fertilization, each cell of the embryo randomly inactivates one X chromosome • This inactivation is permanent (except in germ cells), and all descendants of a particular cell will have the same X chromosome inactivated • Because genes on only one X chromosome are expressed in females, this equalizes the amounts of products from X-linked genes in males and females

Turner syndrome (45, X)

A monosomy of the X chromosome that results in female sterility. • Occurs with a frequency of 1 in 10,000 female births • Females are typically short, wide-chested, with rudimentary ovaries and puffiness of the hands and feet • They may have an aortic constriction, but there is no mental retardation associated with this condition • Significant differences in height, sexual development, hearing, and other physical characteristics

chromosomal translocations

A significant number of cancers, especially leukemia, are associated with specific ____.

• errors in meiosis during gamete formation - if homologous chromosomes fail to separate during meiosis I, the division in meiosis II will produce diploid gametes • events at fertilization - simultaneous fusion of a haploid egg with two haploid sperm (dispermy) • errors in mitosis after fertilization

Abnormalities in the number of chromosomal sets can arise in several ways: • • •

Robertsonian translocation

About 5% of all Down syndrome cases involve a ____, most often between chromosomes 21 and 14.

pseudohermaphroditism (gonadal intersexuality)

Affected individuals have both male and female structures, but at different times in their lives. At early stages of life, phenotypic sex does not match chromosomal sex, but later, the phenotypic sex changes do match chromosomal sex. • XY males initially are phenotypic females but at puberty develop male structures • Product prevents conversion of testosterone to DHT, which in turn results in female genitalia, but with testes. At puberty, increased testosterone secretion transforms genitalia into male structures

Fragile-X syndrome (Martin-Bell Syndrome)

An X chromosome that carries a gap, or break, at band q27; associated with intellectual disability in males. • Two fragile sites on the X chromosome, FRAX E and FRAX A, are associated with genetic disorders • The FRAX A site near the tip of the long arm of the X chromosome is associated with this X-linked form of mental retardation • Caused by a mutation in the FMR-1 gene

anhidrotic ectodermal dysplasia

An X-linked gene controls the formation of sweat glands. A rare recessive mutant allele blocks the formation of sweat glands. Heterozygous women have patches of skin with sweat glands (cells in which the active X chromosome carries the normal allele) and patches of skin without sweat glands (cells in which the active X chromosome carries the mutant allele). • Human equivalent of tortoiseshell/calico cats

complete androgen insensitivity (CAIS)

An x-linked genetic trait that causes XY individuals to develop into phenotypic females. • A mutation in the hormone receptor (AR, androgen receptor) prevents production of receptors for testosterone • So, although DHT and testosterone are present, cells of the embryo cannot respond to their presence • As a result, development proceeds along the default pathway, which is female • The Wolffian duct system degenerates, and external genitalia develop as female structures • Affected individuals are chromosomal males but phenotypic females; they have well-developed breasts, little pubic hair, and do not menstruate

Patau syndrome (trisomy 13)

Aneuploidy involving the presence of an extra copy of chromosome 13. • Occurs in only 1 of 10,000 live births • Is lethal; half of all affected individuals die in the first month • Facial malformations, eye defects, extra fingers or toes, feet with large protruding heels • Severe malformations of the brain and nervous system, congenital heart defects

Edwards syndrome (trisomy 18)

Aneuploidy involving the presence of an extra copy of chromosome 18. • Occurs with a frequency of 1 in 11,000 live births, and the average survival time is 2 to 4 months • Infants are small at birth, grow very slowly, and are mentally retarded • 80% of births are female • Clenched fists, with the second and fifth fingers overlapping the third and fourth fingers, and malformed feet are also characteristic • Heart malformations are almost always present, and heart failure or pneumonia are the usual cases of death

Down syndrome (trisomy 21)

Aneuploidy involving the presence of an extra copy of chromosome 21. • Occurs in about 1 in 800 live births and is a leading cause of childhood mental retardation and heart defects • About 10% are severely retarded—unable to dress, eat, or use the toilet by themselves • Affected individuals usually have a wide, flat skull, folds in the corners of the eyelids, and spots on the irises • They may also have large, furrowed tongues that cause the mouth the remain partially open • Physical growth, behavior, and mental development are retarded, and approximately 40% of all affected children have congenital heart defects • These children are also susceptible to respiratory infections, develop leukemia at a rate far above that of the normal population, and are at high risk for Alzheimer disease • Many survive into adulthood, although few reach the age of 50 years

XYY syndrome

Aneuploidy of the sex chromosomes involving XYY chromosome constitution. • Frequency of XYY males in the general population is 1 in 1000 male births • Phenotypically, most are above average in height, have personality disorders and subnormal intelligence • *No proven antisocial behavior*

Klinefelter syndrome (47, XXY)

Aneuploidy of the sex chromosomes involving an XXY chromosomal constitution. • Occurs in approximately 1 in 1,000 male births • Most males have fertility problems but few other symptoms • About 60% of the cases result from maternal nondisjunction • Other forms have XXYY, XXXY, and XXXXY sex-chromosome sets • Additional X chromosomes in these karyotypes increase the severity of the phenotypic symptoms and bring on clear-cut mental retardation • A significant number of affected males are mosaics--in these cases, nondisjunction occurred during mitosis in embryos

chromosome number, arm, region, band

Any region in the human karyotype can be identified by a descriptive address, such as 1q2.4. This address includes the ____ (1), the ____ (q), the ____ (2), and the ____ (4).

0.05%, 0.9%, 3%

At age 20, the risk of having a child with Down syndrome is ____; by age 35, the risk has climbed to ____; and by age 45, ____ of all newborns have trisomy 21.

X

At least one copy of an ____ chromosome is essential for survival.

Wolffian, Mullerian

Because the ovary does not produce testosterone, the ____ duct system degenerates, and because no AMH is produced, the ____ duct system develops to form the fallopian tubes, the uterus, and parts of the vagina.

fetus

By about 8 to 9 weeks, the embryo is called a ____.

p, q

By convention, the short arm of each chromosome is designated the ____ arm, and the long arm the ____ arm.

metaphase

Chromosomes are usually studied and photographed while they are in ____ of mitosis.

developmental abnormalities, lethal

Deletion of a chromosome region causes ____; deletion of an entire autosome is ____.

12 to 13 weeks

Development between fertilization and birth is divided into three trimesters, each of which last about ____ to ____ weeks.

oxytocin, breech birth

During the last trimester, the cervix softens and the fetus shifts downward, usually with its head pressed against the cervix. Hormone-induced mild uterine contractions start during the third trimester, but at the start of the birth process, they become more frequent and intense. The hormone ____, released from the pituitary gland, helps stimulate uterine contractions. During labor, the cervical opening dilates in stages to allow passage of the fetus, and uterine contractions expel the fetus. The head usually emerges first. If another body part enters the birth canal first, the result is called a ____. A short time after delivery, a second round of uterine contractions begins the expulsion of the placenta.

maternal selection

Embryo-uterine interactions normally result in the miscarriage of chromosomally abnormal embryos—a process called ____. If it becomes less effective as women age, this would allow more chromosomally abnormal embryos to implant and develop

HIV

Fetuses infected with ____ are at risk for being stillborn or born prematurely and with low birth weight.

sex-limited genes

Genes that deal with traits such as breast development in females and facial hair in males are other examples of ____, as are virtually all other genes that deal with secondary sexual characteristics.

amniocentesis and chorionic villus sampling

In a fetus, cells are collected for chromosomal analysis using two methods: • •

clitoris, labia minors, labia majora

In females, no DHT is present, and the genital tubercle develops into the ____, the genital folds form the ____, and the labioscrotal swellings form the ____.

dihydrotestosterone (DHT)

In males, testosterone is converted into the hormone ____, which directs the formation of the external genitalia and influences brain development and organ size. Under its influence, the genital folds and genital tubercle develop into the penis, and labioscrotal swelling forms the scrotum.

• sex-influenced traits • sex-limited traits • imprinted genes

In some cases, males and females differ in the phenotypic expression of a trait. This can arise in three situations: • • •

epididymis, vas deferens, ejaculatory duct, urethra

In the first stage, when a male is sexually aroused, sperm move from the ____ into the ____, that from which each testis joins to form a short ____ that connects to the ____. In the second stage, sperm are propelled by the muscular contractions that accompany orgasm from the vas deferens through the urethra and are expelled from the body.

X inactivation center (Xic)

Inactivation of X chromosomes begins and is regulated from a region on the X chromosome called the ____. One of the first steps is expression of the XIST gene, located in the Xic. When XIST is expressed, the X chromosome becomes coated with XIST RNA. This causes almost all genes on the coated chromosome to become inactivated and form a Barr body. The small region not inactivated is called the pseudoautosomal region and contains genes homologous to those on the Y chromosome. Once an X chromosome is inactivated, all copies made in subsequent cell divisions are also inactivated.

C-banding

Metaphase spreads are chemically treated to extract DNA from the arms but not the centromeric regions of chromosomes, stained with Giemsa stain, and observed with a light microscope. This banding technique yields a darkly-stained C band centromeric region of the chromosome that corresponds to the region of constitutive heterochromatin.

R-banding

Metaphase spreads are heated at high temperatures to achieve partial denaturation of DNA, stained with Giemsa stain, and observed with a light microscope. This banding technique yields darkly-stained R bands that correspond to the light bands in G-banded chromosomes. This pattern is the reverse of G-banding.

Q-banding

Metaphase spreads are treated with the chemical quinacrine mustard, and the fluorescent banding pattern is observed with a special UV light microscope. This banding technique yields bright fluorescent bands upon expose to UV light; same as darkly-stained G bands.

G-banding

Metaphase spreads are treated with trypsin, an enzyme that digests part of chromosomal protein, stained with Giemsa stain, and are observed with a light microscope. This banding technique yields darkly-stained G bands.

50%, chromosome 16

Most autosomal trisomies are lethal during prenatal development and account for up to ____ of the chromosomal abnormalities seen in miscarriages. Trisomy for chromosome ____ accounts for almost 1/3 of all cases.

G-banding

Most karyotypes are prepared using ____.

testosterone, anti-Mullerian hormone (AMH)

Once testis development is initiated by action of the SRY gene, cells in the testis secrete to hormones: ____, which stimulates the Wolffian ducts to form the male internal duct system that will carry sperm, and ____, which is secreted by the developing testis to stop further development of female duct structures and causes the Mullerian ducts to degenerate.

trisomy 21

Only a few autosomal trisomies result in live births (trisomy 8, 13, and 18). ____ (Down syndrome) is the only autosomal trisomy that allows survival into adulthood.

male-lethal X-linked dominant traits

Several X-linked dominant traits are expressed only in females because affected males die before birth. These conditions are called ____ and include orofaciodigital syndrome, incontinentia pigmenti, and focal dermal hypoplasia. Each of these disorders affects multiple systems, including the skeleton, skin, teeth, and central nervous system. All reported cases are females. The exceptions are XXY males.

mosaics

The Lyon hypothesis means that female mammals are actually ____, constructed of two different cell types: Some cells express genes from the mother's X chromosome, and some cells express genes from the father's X chromosome.

human chorionic gonadotropin (hCG)

The chorion makes and releases a hormone called ____ which prevents breakdown of the uterine lining and stimulates endometrial cells to release hormones that help maintain the pregnancy. Home pregnancy tests work by detecting elevated levels of ____ as early as the first day of a missed menstrual period.

trisomy 21

The first chromosomal abnormality discovered in humans.

nondisjunction

The most common cause of aneuploidy. • If occurring in meiosis I, all gametes will be abnormal and carry either both members of a chromosomal pair or neither member of the pair • If occurring in meiosis II, two normal haploid cells and two abnormal cells are produced, one with an extra copy of a chromosome and one missing a chromosome

triploidy

The most common form of polyploidy in humans. A chromosomal number that is three times the haploid number, having three copies of all autosomes and three sex chromosomes. • Approximately 75% of all cases are 69,XYY and have two sets of paternal chromosomes, probably through dispermy • Almost 1% of all conceptions are triploid, but over 99% of those result in miscarriage • Only 1 in 10,000 live births is triploid, but most of these infants die within a month • Triploid newborns have multiple abnormalities, including an enlarged head, fused fingers and toes, and malformations of the mouth, eyes, and genitals

chromosomal sex, gonadal sex, phenotypic sex

The sex of an individual can be defined at several levels: ____, ____, ____.

translocation, duplication, deletion

The symbols for structural abnormalities detected in karyotypes include *t* for a ____, *dup* for ____, and *del* for ____.

• When the mother is over age 35. The risk of having children with chromosome abnormalities increase dramatically after this age, so amniocentesis is recommended for pregnant women who are 35 years or older • When the mother has already had a child with a chromosomal aberration. The recurrence risk in such cases is 1% to 2% • When either parent carries one or more structurally abnormal chromosomes. This situation may cause an abnormal number of chromosomes in a child • When the mother is a carrier of a disorder caused by a gene on the X chromosome. If the mother is a carrier of an X-linked biochemical disorder that cannot otherwise be diagnosed prenatally and is willing to abort if the fetus is male, amniocentesis is recommended • When the couple has had a number of previous miscarriages or unexplained fertility problems

The use of amniocentesis is restricted to certain circumstances: • • • • •

reciprocal translocations, Robertsonian translocations

There are two major types of translocations: • •

0.2% to 0.3%

There is a ____ to ____ risk of miscarriage with amniocentesis and a small risk of maternal infection.

15% to 18%

Triploidy is found in ____ to ____ of all miscarriages.

False; aneuploidy of the sex chromosomes is more common than autosomal aneuploidy

True or false? Aneuploidy involving the autosomes is more common than aneuploidy involving the X and Y chromosomes.

True

True or false? CVS is used less frequently than amniocentesis, but the risk of miscarriage is about the same as for amniocentesis.

True

True or false? CVS offers early diagnosis of genetic diseases, and if termination of pregnancy is elected, maternal risks are lower at 9 to 12 weeks than at 16 weeks.

True

True or false? Defects produced by teratogens are nongenetic and are not passed on to the following generations.

Wolffian duct, Mullerian duct

Two internal duct systems are the ____ (male) and the ____ (female) ducts. The second step in normal sex differentiation begins around 8 to 9 weeks when gene expression activates different developmental pathways and causes the undifferentiated gonads to develop as testes or ovaries. This step--gonadal sex differentiation--takes place over the next 4 to 6 weeks.

fragile sites

____ appear as gaps or breaks at specific sites on a chromosome and are inherited as codominant traits. Spontaneous chromosome breaks often occur at these sites, producing chromosome fragments, deletions, and other aberrations.

Duchenne Muscular Dystrophy (DMD)

____ is an X-linked recessive disorder that, for all practical purposes, is a sex-limited trait. It affects 1 in 3,500 males and about 1 in 50,000,000 females.

pattern baldness

____ is an example of a sex-influenced trait that is expressed more often in males than in females.

radiation

____, especially medical x-rays, can be a teratogen. Pregnant women should avoid all unnecessary x-rays, and all females should have abdominal shielding for x-ray procedures.

oocyte

a cell from which an ovum develops by meiosis

polyploidy

a chromosomal number that is a multiple of the normal haploid chromosomal set

aneuploidy

a chromosomal number that is not an exact multiple of the haploid set

karyotype

a complete set of chromosomes from a cell that has been photographed during cell division and arranged in a standard sequence

trisomy

a condition in which one chromosome is present in three copies, whereas all others are diploid; having one more than the diploid number (2n + 1)

monosomy

a condition in which one member of a chromosomal pair is missing; having one less than the diploid number (2n - 1)

barr body

a densely staining mass in the somatic nuclei of mammalian females; an inactivated X chromosome

follicle

a developing egg surrounded by an outer layer of follicle cells, contained in the ovary

vas deferens

a duct connected to the epididymis, which sperm travels through

oviduct

a duct with fingerlike, ciliated channels partially surrounding the ovary and connecting to the uterus, through which oocytes are conducted from an ovary to the uterus; also called the fallopian, or uterine tube; usual site of fertilization

SRY

a gene, called the sex-determining region of the Y, located near the end of the short arm of the Y chromosome that plays a major role in causing the undifferentiated gonad to develop into a testis

prostate gland

a gland that secretes a milky, alkaline fluid that neutralizes acidic vaginal secretions and enhances sperm viability

uterus

a hollow, pear-shaped muscular organ where an early embryo will implant and develop throughout pregnancy

dosage compensation

a mechanism that regulates the expression of sex-linked genes; it equalizes the amount of X chromosome gene products in both sexes

chorionic villus sampling (CVS)

a method of sampling fetal chorionic cells by inserting a catheter through the vagina or abdominal wall into the uterus to remove a sample of fetal tissue from the chorion; used in diagnosing biochemical and cytogenic defects in the embryo; usually performed in the eighth or ninth week of pregnancy

amniocentesis

a method of sampling the fluid surrounding the developing fetus by inserting a hollow needle through the abdominal and uterine walls into the amniotic sac and withdrawing suspended fluid and fetal cells shed from the skin, respiratory tract, and urinary tract of the fetus; approximately 10 to 30 ml of fluid is withdrawn by syringe; used in diagnosing fetal genetic and developmental disorders; usually performed in the 16th week of pregnancy

semen

a mixture of sperm and various glandular secretions containing 5% spermatozoa

epididymis

a part of the male reproductive system where sperm mature and are stored

scrotum

a pouch of skin outside the male body that contains the testes

centromere

a region of a chromosome to which spindle fibers attach during cell division; its location gives a chromosome its characteristic shape

pattern baldness

a sex-influenced trait that acts like an autosomal dominant trait in males and an autosomal recessive trait in females

thalidomide

a tranquilizer prescribed to stop morning sickness, which caused limb defects in unborn children

urethra

a tube that passes from the bladder and opens to the outside; it functions in urine transport and, in males, also carries sperm

teratogen

any physical or chemical agent that brings about an increase in congenital malformations

autosomes

chromosomes other than the sex chromosomes; in humans, chromosomes 1 to 22 are autosomes

submetacentric

chromosomes with a centromere located at a distance from the center that also have arms of unequal length

acrocentric

chromosomes with a centromere located very close to one end that also have arms of unequal length

metacentric

chromosomes with centrally located centromeres that have arms of equal length

spermatocytes

diploid cells that undergo meiosis to form haploid spermatids

ovaries

female gonads that produce oocytes and female sex hormones called estrogens

seminal vesicles

glands in males that secrete fructose and prostaglandins into the semen

bulbourethral glands

glands in the male that secrete a mucus-like substance that provides lubrication for intercourse

sex chromosomes

in humans, the X and Y chromosomes that are involved in sex determination

ejaculatory duct

in males, a short connector from the vas deferens to the urethra

prostaglandins

locally acting chemical messengers that stimulate contraction of the female reproductive system to assist in sperm movement

sex-limited genes

loci that produce a phenotype in only one sex

sperm

male gamete

testes

male gonads that produce spermatozoa and male sex hormones called androgens

ovary

once of a pair of primary reproductive organs in which oocytes (immature eggs) form and mature; produces hormones (estrogens and progesterone), which simulate maturation of oocytes, formation of corpus luteum (a glandular structure), and preparation of the uterine lining for pregnancy

gonads

organs where gametes are produces

telomere

short repeated DNA sequences located at each end of chromosomes

seminiferous tubules

small, tightly coiled tubes inside the testes where sperm are produced

blastocyst

the developmental stage at which the embryo implants into the uterine wall; it is made up of about 100 cells and has several parts: the inner cell mass, an internal cavity, and an outer layer of cells called the trophoblast

nondisjunction

the failure of homologous chromosomes to separate properly during meiosis or mitosis

zygote

the fertilized egg that develops into a new individual

endometrium

the inner lining of the uterus that is shed at menstruation if fertilization has not occurred; it is the site of implantation of blastocyst; becomes thickened, nutrient-packed, highly vascularized tissue every month in preparation for a pregnancy; gives rise to the maternal portion of the placenta, an organ that metabolically supports embryonic and fetal development

cervix

the lower neck of the uterus, opening into the vagina; secretes mucus that helps sperm move into the uterus and bars many bacteria

vagina

the opening that receives the penis during intercourse and also serves as the birth canal

spermatogenesis

the process of sperm production

ovulation

the release of a secondary oocyte from the follicle; usually occurs monthly during a female's reproductive lifetime

myometrium

thick muscle layers of the uterus that stretch enormously during pregnancy

sex-influenced traits

traits controlled by autosomal genes that are usually dominant in one sex but recessive in the other sex

reciprocal translocation

two nonhomologous chromosomes exchange parts, or segments

gametes

unfertilized germ cells

second trimester

• Bony parts of the skeleton begin to form • The heartbeat can be heard with a stethoscope • The mother can feel movements of the fetus's arms and legs • At the end of this phase, the fetus weighs about 700 g (or 27 oz) and is 30 to 40 cm long • The fetus has a well-formed face, its eyes can open, and it has fingernails and toenails

first trimester

• The embryo grows from 5 mm to 9 cm in length • The head is very large in relation to the rest of the body because of the rapid development of the nervous system • The fetus weighs about 15g, or half an ounce by the end of this phase • All the major organ systems have formed and are functional • *Most of the important events in human development occur during this stage*

third trimester

• The fetus grows rapidly during this trimester • The circulatory and respiratory systems mature to prepare for breathing air • Maternal nutrition is crucial for development of the fetal brain and nervous system • The calcium in the mother's diet is used to develop the fetal skeletal system • The fetus doubles in size, and chances for survival outside the uterus increase rapidly • Antibodies are passed from the mother to the fetus, giving the fetus a temporary immune system • At the end of this trimester, the fetus is about 50 cm long and weighs from 5.5 to 10.5 lbs